The pancreas functions as an exocrine ground that secretes digestive enzymes such as pancreas lipase, trypsin, elastase, pancreas amylase and also as an endocrine gland that secretes pancreatic hormones such as glucagon, insulin, somatostatin, and the pancreatic polypeptide (PP). Recently, it has been reported that ghrelin which is a gastric hormone is also secreted from the endocrine gland cells in the pancreas. The pancreatic hormones are produced by the cell mass in the pancreas called pancreatic islet which consists of four types of cells including α cells, β cells, δ cells and PP cells.
Insulin plays an important role in the control of the blood sugar level within a suitable amount. Insulin promotes the use of glucose, the synthesis of proteins and the production and storage of neutral fats and thereby lowers the blood sugar level. Glucagon also plays an important role together with insulin in the regulation of the glycometabolism. This hormone increases the blood sugar level through glycogenesis in the liver or gluconeogenesis. Somatostatin inhibits secretion of various hormones from pancreas. This hormone is activated via binding with somatostatin receptors. PP is a hormone secreted by Langerhans islets in response to food intake and is known as “satiety hormone”. This hormone lowers food intake or weight increase. Ghrelin stimulates food intake and lowers oxidization of fats, and causes weight gain.
Diabetes is a disease that is developed due to a shortage or insufficient working of insulin. Once developed in a patient, the disease is hard to be cured completely. There are two major types of diabetes, type 1 diabetes that is also known as insulin-dependent diabetes and type 2 diabetes that is also known as insulin-independent diabetes.
Type 2 diabetes is a chronic disease that is developed where the body acquires insulin resistance. Type 2 diabetes is also known as a lifestyle-related disease developed due to bad lifestyle habitat including obesity or stress caused by overeating or lack of excise. Type 2 diabetes often occurs in the middle aged and elderly people. Many of diabetic patients have Type 2 diabetes.
Type 1 diabetes is caused by destruction of the beta cells or insulin producing cells by an autoimmune disease or viral infection. The insulin producing cells are destroyed and insulin is not secreted in the body. The patients with type 1 diabetes are administered with insulin as a symptomatic treatment. In addition, pancreas or islet transplantation has been applied so that the patient acquires the ability to control the blood sugar level automatically. The blood sugar level always fluctuates and the pancreas or islet transplantation could reduce the burden on the patients. This treatment could achieve the normal blood-sugar level in the patient. However, only insufficient number of pancreas and islets has been available for transplantation at present. The patient received transplantation must take an immunosuppressant for a lifetime and such a drug may cause infectious diseases or other side effects.
A treatment of type I diabetes including inducing insulin producing cells from the cells derived from the patient in vitro and transplanting the induced insulin producing cells to the patient's body has been proposed. For example, procedures to induce insulin producing cells in vitro from patient's own pancreas-tissue stem cells or pancreatic duct epithelium. Transplantation using insulin producing cells derived from patient's own cells is advantageous in safety and is free from the problem of immune rejection.
Methods for generating insulin producing cells known to the art include differentiating pluripotent stem cells such as embryonic stem (ES) cells or induced stem (iPS) cells, differentiating pancreas tissue stem cells, obtaining pancreatic duct epithelial cells from the body and differentiating the cells outside the body.
Methods for inducing insulin producing cells from pluripotent stem cells known to the art include inducing differentiation by using activin and retinoic acid (RA) (Patent Literature 1 and Non-Patent Literatures 1-5). In addition, insulin producing cells may also be induced by introducing PDX1 into pluripotent stem cells and culturing the same (Patent Literature 2 and 3), applying a combination of plurality of small molecule compounds to pluripotent stem cells to generate insulin-producing cells (patent literature 4 and non-patent literature 6).